Skip to main content

Advertisement

SpringerLink
Log in

CircSCMH1 Accelerates Sorafenib Resistance in Hepatocellular Carcinoma by Regulating HN1 Expression via miR-485-5p

  • Original Paper
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

Sorafenib (SOR) is the first-line chemotherapeutic therapy for hepatocellular carcinoma (HCC) treatment, but SOR resistance is a key factor affecting the therapeutic effect. Emerging studies have suggested that circular RNAs (circRNAs) play an important role in the development of drug resistance in HCC cells. This paper aimed to elucidate the potential role and molecular mechanism of circRNA Scm polycomb group protein homolog 1 (circSCMH1) in SOR-resistant HCC cells. CircSCMH1, microRNA-485-5p (miR-485-5p), and hematological and neurological expressed 1 (HN1) contents were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK8) assay was adopted to detect the SOR sensitivity of cells. Cell proliferation, migration, invasion, and apoptosis were assessed using colony formation, 5-Ethynyl-2’-deoxyuridine (EdU), transwell, and flow cytometry assays. Glucose metabolism was analyzed using commercial kits. HN1, B cell lymphoma-2 (Bcl-2), and Bcl-2-associated X (Bax) protein levels were assessed using western blot. Binding between miR-485-5p and circSCMH1 or HN1 was verified using a dual-luciferase reporter. Xenograft tumor model was used to explore the function of circSCMH1 in vivo. CircSCMH1 expression and HN1 abundances were increased, but the miR-485-5p level was reduced in SOR-resistant HCC tissues and cells. Deficiency of circSCMH1 enhanced SOR sensitivity by suppressing cell proliferation, migration, invasion, and glucose metabolism and inducing cell apoptosis in SOR-resistant HCC cell lines (Huh7/SOR and Hep3B/SOR). Mechanistically, circSCMH1 sponged miR-485-5p to positively regulate HN1 expression. Importantly, circSCMH1 depletion inhibited tumor growth and increased SOR sensitivity in vivo. CircSCMH1 promoted SOR resistance in HCC cells at least partly through upregulating HN1 expression by sponging miR-485-5p. These findings elucidated a new regulatory pathway of chemo-resistance in SOR-resistant HCC cells and provided a possible circRNA-targeted therapy for HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The analyzed datasets generated during the present study are available from the corresponding author on reasonable request.

References

  1. Heimbach, J. K., Kulik, L. M., Finn, R. S., Sirlin, C. B., Abecassis, M. M., Roberts, L. R., Zhu, A. X., Murad, M. H., & Marrero, J. A. (2018). AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 67(1), 358–380.

    Article  PubMed  Google Scholar 

  2. Diaz-Gonzalez, A., Reig, M., & Bruix, J. (2016). Treatment of hepatocellular carcinoma. Digestive Diseases, 34(5), 597–602.

    Article  PubMed  Google Scholar 

  3. Colecchia, A., Schiumerini, R., Cucchetti, A., Cescon, M., Taddia, M., Marasco, G., & Festi, D. (2014). Prognostic factors for hepatocellular carcinoma recurrence. World Journal of Gastroenterology, 20(20), 5935–5950.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fujiwara, N., Friedman, S. L., Goossens, N., & Hoshida, Y. (2018). Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. Journal of Hepatology, 68(3), 526–549.

    Article  PubMed  Google Scholar 

  5. Adnane, L., Trail, P. A., Taylor, I., & Wilhelm, S. M. (2006). Sorafenib (BAY 43–9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods in Enzymology, 407, 597–612.

    Article  CAS  PubMed  Google Scholar 

  6. Hosseinzadeh, F., et al. (2022). The effects of Sorafenib and Natural killer cell co-injection in combinational treatment of hepatocellular carcinoma; an in vivo approach. Pharmacological reports : PR, 74(2), 379–391.

    Article  CAS  PubMed  Google Scholar 

  7. Xia, S., Pan, Y., Liang, Y., Xu, J., & Cai, X. (2020). The microenvironmental and metabolic aspects of sorafenib resistance in hepatocellular carcinoma. eBioMedicine, 51, 102610.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li, W., et al. (2019). LncRNA SNHG1 contributes to sorafenib resistance by activating the Akt pathway and is positively regulated by miR-21 in hepatocellular carcinoma cells. Journal of experimental & clinical cancer research : CR, 38(1), 183.

    Article  CAS  PubMed Central  Google Scholar 

  9. Hsu, C. H., Shen, Y. C., Shao, Y. Y., Hsu, C., & Cheng, A. L. (2014). Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. Journal of hepatocellular carcinoma, 1, 85–99.

    PubMed  PubMed Central  Google Scholar 

  10. Li, J. F., & Song, Y. Z. (2017). Circular RNA GLI2 promotes osteosarcoma cell proliferation, migration, and invasion by targeting miR-125b-5p. Tumour Biology, 39(7), 1010428317709991.

    Article  PubMed  Google Scholar 

  11. Liang, H. F., Zhang, X. Z., Liu, B. G., Jia, G. T., & Li, W. L. (2017). Circular RNA circ-ABCB10 promotes breast cancer proliferation and progression through sponging miR-1271. American Journal of Cancer Research, 7(7), 1566–1576.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Yao, Z., et al. (2017). ZKSCAN1 gene and its related circular RNA (circZKSCAN1) both inhibit hepatocellular carcinoma cell growth, migration, and invasion but through different signaling pathways. Molecular Oncology, 11(4), 422–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao, L., Ma, N., Liu, G., Mao, N., Chen, F., & Li, J. (2021). Lidocaine Inhibits Hepatocellular Carcinoma Development by Modulating circ_ITCH/miR-421/CPEB3 Axis. Digestive Diseases and Sciences, 66(12), 4384–4397.

    Article  CAS  PubMed  Google Scholar 

  14. Wei, Y., et al. (2020). A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma. Hepatology, 71(1), 130–147.

    Article  CAS  PubMed  Google Scholar 

  15. Yu, J., et al. (2018). Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. Journal of Hepatology, 68(6), 1214–1227.

    Article  CAS  PubMed  Google Scholar 

  16. Cao, S., Wang, G., Wang, J., Li, C., & Zhang, L. (2019). Hsa_circ_101280 promotes hepatocellular carcinoma by regulating miR-375/JAK2. Immunology and Cell Biology, 97(2), 218–228.

    Article  CAS  PubMed  Google Scholar 

  17. Sun, R., Li, H., Li, J., Shen, S., Cui, G., & Dong, G. (2020). CircRNA circ-0038718 promotes hepatocellular carcinoma progression through sponging miR-139-3p. Biochemical and Biophysical Research Communications, 533(4), 845–852.

    Article  CAS  PubMed  Google Scholar 

  18. Ren, L., Zhai, H., Wang, X. L., Li, J. Z., & Xia, Y. H. (2020). Hsa_circ_0011946 promotes the migration and invasion of hepatocellular carcinoma by inducing EMT process. European Review for Medical and Pharmacological Sciences, 24(3), 1108–1115.

    CAS  PubMed  Google Scholar 

  19. Catalanotto, C., Cogoni, C., Zardo, G.: MicroRNA in control of gene expression: an overview of nuclear functions. International Journal of Molecular Sciences 17(10) (2016)

  20. Lv, L., & Wang, X. (2018). MicroRNA-296 targets specificity protein 1 to suppress cell proliferation and invasion in cervical cancer. Oncology Research, 26(5), 775–783.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Shi, D. M., et al. (2018). miR-296-5p suppresses EMT of hepatocellular carcinoma via attenuating NRG1/ERBB2/ERBB3 signaling. Journal of Experimental & Clinical Cancer Research, 37(1), 294.

    Article  CAS  Google Scholar 

  22. Zhou, S. L., Tang, Q. L., Zhou, S. X., & Ren, R. Z. (2019). MiR-296-5p suppresses papillary thyroid carcinoma cell growth via targeting PLK1. European Review for Medical and Pharmacological Sciences, 23(5), 2084–2091.

    PubMed  Google Scholar 

  23. Liu, S., Wang, H., Mu, J., Wang, H., Peng, Y., Li, Q., Mao, D., & Guo, L. (2020). MiRNA-211 triggers an autophagy-dependent apoptosis in cervical cancer cells: regulation of Bcl-2. Naunyn-Schmiedeberg’s archives of pharmacology, 393(3), 359–370.

    Article  CAS  PubMed  Google Scholar 

  24. Hua, F. F., Liu, S. S., Zhu, L. H., Wang, Y. H., Liang, X., Ma, N., & Shi, H. R. (2017). MiRNA-338-3p regulates cervical cancer cells proliferation by targeting MACC1 through MAPK signaling pathway. European review for medical and pharmacological sciences, 21(23), 5342–5352.

    PubMed  Google Scholar 

  25. Sun, X., Liu, Y., Li, M., Wang, M., & Wang, Y. (2015). Involvement of miR-485-5p in hepatocellular carcinoma progression targeting EMMPRIN. Biomedicine & Pharmacotherapy, 72, 58–65.

    Article  CAS  Google Scholar 

  26. Laughlin, K. M., Luo, D., Liu, C., Shaw, G., Warrington, K. H., Jr., Qiu, J., Yachnis, A. T., & Harrison, J. K. (2009). Hematopoietic- and neurologic-expressed sequence 1 expression in the murine GL261 and high-grade human gliomas. Pathology Oncology Research, 15(3), 437–444.

    Article  CAS  PubMed  Google Scholar 

  27. Zhou, G., Wang, J., Zhang, Y., Zhong, C., Ni, J., Wang, L., Guo, J., Zhang, K., Yu, L., & Zhao, S. (2004). Cloning, expression and subcellular localization of HN1 and HN1L genes, as well as characterization of their orthologs, defining an evolutionarily conserved gene family. Gene, 331, 115–123.

    Article  CAS  PubMed  Google Scholar 

  28. Petroziello, J., Yamane, A., Westendorf, L., Thompson, M., McDonagh, C., Cerveny, C., Law, C. L., Wahl, A., & Carter, P. (2004). Suppression subtractive hybridization and expression profiling identifies a unique set of genes overexpressed in non-small-cell lung cancer. Oncogene, 23(46), 7734–7745.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang, C., Xu, B., Lu, S., Zhao, Y., & Liu, P. (2017). HN1 contributes to migration, invasion, and tumorigenesis of breast cancer by enhancing MYC activity. Molecular Cancer, 16(1), 90.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Alkan, A. H., & Akgül, B. (2022). Endogenous miRNA Sponges. Methods in molecular biology (Clifton, NJ), 2257, 91–104.

    Article  CAS  Google Scholar 

  31. Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495(7441), 384–388.

    Article  ADS  CAS  PubMed  Google Scholar 

  32. Liu, C., Wu, J., Chang, Z.: Trends and age-period-cohort effects on the prevalence, incidence and mortality of hepatocellular carcinoma from 2008 to 2017 in Tianjin, China. International Journal of Environmental Research and Public Health 18(11) (2021)

  33. Liu, Z., Jiang, Y., Yuan, H., Fang, Q., Cai, N., Suo, C., Jin, L., Zhang, T., & Chen, X. (2019). The trends in incidence of primary liver cancer caused by specific etiologies: results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention. Journal of Hepatology, 70(4), 674–683.

    Article  PubMed  Google Scholar 

  34. Roxburgh, P., & Evans, T. R. (2008). Systemic therapy of hepatocellular carcinoma: are we making progress? Advances in Therapy, 25(11), 1089–1104.

    Article  CAS  PubMed  Google Scholar 

  35. Kim, D. W., Talati, C., & Kim, R. (2017). Hepatocellular carcinoma (HCC): beyond sorafenib-chemotherapy. J Gastrointest Oncol, 8(2), 256–265.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Aishanjiang, K., et al. (2021). Circular RNAs and hepatocellular carcinoma: new epigenetic players with diagnostic and prognostic roles. Frontiers in oncology, 11, 653717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, P., et al. (2022). circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma. Molecular Therapy : The Journal of the American Society of Gene Therapy, 30(1), 431–447.

    Article  CAS  PubMed  Google Scholar 

  38. Xu, J., et al. (2020). CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal transduction and targeted therapy, 5(1), 298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou, J., Zhang, W. W., Peng, F., Sun, J. Y., He, Z. Y., & Wu, S. G. (2018). Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3. Cancer Management and Research, 10, 535–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wei, H., Li, J., Xie, C., & Dong, H. (2022). Circular RNA hsa_circ_0011946 promotes the malignant process of salivary adenoid cystic carcinoma by downregulating miR-1205 expression. Experimental and Therapeutic Medicine, 23(4), 295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Qiu, F., Qiao, B., Zhang, N., Fang, Z., Feng, L., Zhang, S., & Qiu, W. (2021). Blocking circ-SCMH1 (hsa_circ_0011946) suppresses acquired DDP resistance of oral squamous cell carcinoma (OSCC) cells both in vitro and in vivo by sponging miR-338-3p and regulating LIN28B. Cancer Cell International, 21(1), 412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Panda, A. C. (2018). Circular RNAs Act as miRNA sponges. Advances in Experimental Medicine and Biology, 1087, 67–79.

    Article  ADS  CAS  PubMed  Google Scholar 

  43. Liu, H., Hu, G., Wang, Z., Liu, Q., Zhang, J., Chen, Y., Huang, Y., Xue, W., Xu, Y., & Zhai, W. (2020). circPTCH1 promotes invasion and metastasis in renal cell carcinoma via regulating miR-485-5p/MMP14 axis. Theranostics, 10(23), 10791–10807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang, X., Zhou, X., Zeng, F., Wu, X., & Li, H. (2020). miR-485-5p inhibits the progression of breast cancer cells by negatively regulating MUC1. Breast cancer (Tokyo, Japan), 27(4), 765–775.

    Article  PubMed  Google Scholar 

  45. Pan, Y., Qin, J., Sun, H., Xu, T., Wang, S., & He, B. (2020). MiR-485-5p as a potential biomarker and tumor suppressor in human colorectal cancer. Biomarkers in Medicine, 14(3), 239–248.

    Article  CAS  PubMed  Google Scholar 

  46. Yang, L., Deng, W. L., Zhao, B. G., Xu, Y., Wang, X. W., Fang, Y., & Xiao, H. J. (2022). FOXO3-induced lncRNA LOC554202 contributes to hepatocellular carcinoma progression via the miR-485-5p/BSG axis. Cancer Gene Therapy, 29(3–4), 326–340.

    Article  CAS  PubMed  Google Scholar 

  47. Tu, J., Zhao, Z., Xu, M., Chen, M., Weng, Q., Ji, J.: LINC00460 promotes hepatocellular carcinoma development through sponging miR-485-5p to up-regulate PAK1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 118, 109213 (2019)

  48. Gao, J., Dai, C., Yu, X., Yin, X. B., & Zhou, F. (2020). microRNA-485-5p inhibits the progression of hepatocellular carcinoma through blocking the WBP2/Wnt signaling pathway. Cellular Signalling, 66, 109466.

    Article  CAS  PubMed  Google Scholar 

  49. Feng, J., Liu, Y., Fang, T., Zhu, J., Wang, G., & Li, J. (2023). Hematological and neurological expressed 1 (HN1) activates c-Myc signaling by inhibiting ubiquitin-mediated proteasomal degradation of c-Myc in hepatocellular carcinoma. Cell Biology International, 47(3), 560–572.

    Article  CAS  PubMed  Google Scholar 

  50. Chen, J. J., Sun, X., Mao, Q. Q., Jiang, X. Y., Zhao, X. G., Xu, W. J., & Zhong, L. (2020). Increased expression of hematological and neurological expressed 1 (HN1) is associated with a poor prognosis of hepatocellular carcinoma and its knockdown inhibits cell growth and migration partly by down-regulation of c-Met. The Kaohsiung Journal of Medical Sciences, 36(3), 196–205.

    Article  CAS  PubMed  Google Scholar 

  51. Wang, R., Fu, Y., Yao, M., Cui, X., Zhao, Y., Lu, X., Li, Y., Lin, Y., & He, S. (2022). The HN1/HMGB1 axis promotes the proliferation and metastasis of hepatocellular carcinoma and attenuates the chemosensitivity to oxaliplatin. The FEBS Journal, 289(20), 6400–6419.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

This work was supported by Deep Science and Technology Innovation [2014] 109 .

Author information

Authors and Affiliations

  1. Department of Surgery and Oncology, The First Affiliated Hospital of Shenzhen University Health Science Center, No. 3002 Sungang West Road, Futian District, Shenzhen, Guangdong, China

    Meixiang Li, Xionghao Pang, Haixia Xu & Liang Xiao

Authors
  1. Meixiang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xionghao Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Haixia Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XP and HX: Conceptualization and Methodology. HX and LX: Formal analysis and Data curation. ML and XP Validation and Investigation. ML, XP and HX: Writing—original draft preparation and Writing—review and editing of the manuscript. All authors: Approval of final manuscript.

Corresponding author

Correspondence to Liang Xiao.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

The present study was approved by the ethical review committee of The First Affiliated Hospital of Shenzhen University Health Science Center. Written informed consent was obtained from all enrolled patients.

Consent for publication

Patients agree to participate in this work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Pang, X., Xu, H. et al. CircSCMH1 Accelerates Sorafenib Resistance in Hepatocellular Carcinoma by Regulating HN1 Expression via miR-485-5p. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01054-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12033-024-01054-4

Keywords

Search

Navigation